1. Field of the Invention
This invention relates to pharmaceutical compositions containing (−)-hydroxycitric acid useful for reducing inflammation and regulating inflammatory responses and processes.
2. Description Of Prior Art
Chronic inflammation recently has received interest as a suspected cause and/or as a contributory factor in a variety of disease conditions. Perhaps most prominent among such conditions are cardiovascular diseases, although cancers, similarly, are often viewed as being developmentally related to chronic inflammation. At least one half of all cardiovascular events occur in the absence of any serum lipids abnormalities. (Koenig W. Inflammation and coronary heart disease: an overview. Cardiol Rev. 2001 January-February;9(1):31-5) Markers of inflammation typically are present not only on these occasions, but also in diabetes and in related metabolic and circulatory conditions. (Festa A, et al. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000 Jul. 4;102(1):42-7) C-reactive protein (CRP), a primary and sensitive albeit non-specific marker of chronic inflammation, is now the object of considerable attention as a result. Furthermore, for many years it has been realized that other components of the immune system are similary involved in cardiovascular disease, for instance, interleukin-6 (IL-6). (Staels B, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature. 1998 Jun. 25;393(6687):790-3) Tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), fibrinogen, plasminogen activator inhibitor-1, and microabuminuria are among the other recognized markers and causative factors in inflammation, with TNF-α perhaps being the most significant of these.
(−)-Hydroxycitric acid (abbreviated herein as HCA), a naturally-ocurring substance found chiefly in fruits of the species of Garcinia, and several synthetic derivatives of citric acid have been investigated extensively in regard to their ability to inhibit the production of fatty acids from carbohydrates, to suppress appetite, and to inhibit weight gain. (Sullivan A C, Triscari J. Metabolic regulation as a control for lipid disorders. I. Influence of (−)-hydroxycitrrate on experimentally induced obesity in the rodent. American Journal of Clinical Nutrition 1977;30:767-775)
Weight loss benefits were first ascribed to HCA, its salts and its lactone in U.S. Pat. No. 3,764,692 granted to John M. Lowenstein in 1973. The claimed mechanisms of action for HCA, most of which were originally put forth by researchers at the pharmaceutical firm of Hoffmann-La Roche, have been summarized in at least two United States patents. In U.S. Pat. No. 5,626,849 these mechanisms are given as follows: “(−) HCA reduces the conversion of carbohydrate calories into fats. It does this by inhibiting the actions of ATP-citrate lyase, the enzyme which converts citrate into fatty acids and cholesterol in the primary pathway of fat synthesis in the body. The actions of (−) HCA increase the production and storage of glycogen (which is found in the liver, small intestine and muscles of mammals) while reducing both appetite and weight gain. (−) Hydroxycitric acid also causes calories to be burned in an energy cycle similar to thermogenesis . . . (−) HCA also increases the clearance of LDL cholesterol . . . ” U.S. Pat. No. 5,783,603 further argues that HCA serves to disinhibit the metabolic breakdown and oxidation of stored fat for fuel via its effects upon the compound malonyl CoA and that gluconeogenesis takes place as a result of this action. The position that HCA acts to unleash fatty acid oxidation by negating the effects of malonyl CoA with gluconeogenesis as a consequence (McCarty M F. Promotion of hepatic lipid oxidation and gluconeogenesis as a strategy for appetite control. Medical Hypotheses 1994;42:215-225) is maintained in U.S. Pat. No. 5,914,326.
Almost all of the primary research performed on HCA was carried out by Hoffman-La Roche nearly three decades ago. The conclusion of the Roche researchers was that “no significant differences in plasma levels of glucose, insulin, or free fatty acids were detected in (−)-hydroxycitrate-treated rats relative to controls. These data suggest that peripheral metabolism, defined in the present context as metabolite flux, may be involved in appetite regulation . . . ” (Sullivan, Ann C. and Joseph Triscari. Possible interrelationhip between metabolite flux and appetite. In D. Novin, W. Wyriwicka and G. Bray, eds., Hunger: Basic Mechanisms and Clinical Implications (New York: Raven Press, 1976) 115-125.)
Quite surprisingly, HCA has been discovered by the inventor to reduce inflammation. This use is particularly surprising for at least three reasons. First, no existing literature teaches such a role despite more than three decades of active research on the compound.
Second, in a United States patent application (CIP 60/225,821 with IPN WO 02/14477 A2) by Majeed, et al., which advocates the concurrent administration of HCA and the anthocyanin garcinol, looked at the action of garcinol against an inflammation-promoter challenge, but did not extend this to HCA. (Example 2 found on page 11, lines 14-30.) The casual reader would take the work of these authors as actually indicating that HCA does not influence inflammation. Even though the inventors clearly were concerned with inflammation, they equally obviously did not realize that HCA itself has anti-inflammatory properties.
Garcinol can be viewed as an antioxidant, and this brings up a useful distinction between antioxidants and anti-inflammatory compounds. Antioxidants act as electron donors and often are viewed as being anti-inflammatory. Two mistakes follow from this line of thought. First, many powerful anti-inflammatory compounds are not antioxidants, for instance, the omega-3 fatty acids. Second, it is easy to forget that any number of antioxidants are pro-inflammatory in animals and man, indeed, are toxic. Hence, there is concern over the common use in foodstuffs of the antioxidants BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene) and ethoxyquin, all of which can cause allergies and kidney problems, with the first two also possessing liver toxicity and the latter also possessing thyroid toxicity. Moreover, even medically accepted antioxidants, such as alpha-tocopherol and vitamin C, can act as pro-oxidants under a variety of circumstances. In those circumstances under which alpha-tocopherol does act as anti-inflammatory, it shows this effect only at extremely high dosages. (Thomas S R, et al. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001 April;21(4):585-93) With the recent spectacular failures of several long term trials using vitamin E to reduce heart disease, a number of researchers are asking whether chronically-ingested high doses of many antioxidants do not, in fact, lead to reverse effects. Moreover, the benefits of antioxidants in reducing aspects of cardiovascular disease may be unrelated to inflammation, which even with long term usage may not be improved. (Bruunsgaard H, et al. Long-term combined supplementations with alpha-tocopherol and vitamin C have no detectable anti-inflammatory effects in healthy men. J Nutr. 2003 April;133(4):1170-3)
A third reason that the present inventor's discovery is surprising is that at least one company (InterHealth Nutraceuticals) has trumpeted claims that HCA increases the production of serotonin, both in the brain and peripherally. InterHealth-associated researchers have claimed that HCA increases the release of serotonin in the brain and the gut. (Ohia S E, et al. Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX). Mol Cell Biochem. 2002 September;238(1-2):89-103) Such findings, if verified by others, could be taken to imply that a pro-inflammatory effect might be expected from HCA. The findings themselves are highly problematic. However, if true, they make the present inventor's discovery all the more unexpected.
Serotonin is a pro-inflammatory compound with both direct and indirect actions. (Harbuz M S, et al. Alteration of central serotonin modifies onset and severity of adjuvant-induced arthritis in the rat. Br J Rheumatol. 1998 October;37(10):1077-83.) Not only is serotonin a direct inflammatory agent, but even when its serum levels are not implicated, its elevation in particular body compartments is linked to increases in agents, such as IL-6, that alter immune function toward sustaining greater rates of inflammation. (Pichler R, et al. Pro-inflammatory role of serotonin and interleukin-6 in arthritis and spondyloarthropathies—measurement of disease activity by bone scan and effect of steroids. Scand J Rheumatol. 2002;31(1):41-3) Possible positive benefits of serotonin in the downregulation of TNF-α appear only at extreme levels and only in response to massive trauma. (Cloez-Tayarani I, et al. Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine(2A) receptors. Int Immunol. 2003 February;15(2):233-40)
A presumably unanswerable objection to the InterHealth claims is the fact that HCA does not cross the blood-brain barrier, hence the assertions made based upon actions of the compound in vitro with brain slices cannot be extrapolated to live animals. Some early preliminary work showed that labeled 14C attached to HCA found its way into the brain. (Sullivan A C, Triscari J. Metabolic regulation as a control for lipid disorders. I. Influence of (−)-hydroxycitrate on experimentally induced obesity in the rodent. American Journal of Clinical Nutrition 1977;30:767-775) However, work published by the same authors at a later date indicated otherwise. “Hydroxycitrate, chlorocitrate, and epoxyaconitate, compounds that are structurally similar to the tricarboxylic acid cycle intermediate citric acid, but that differ markedly in biochemical activity, have recently been evaluated in animals for effects on appetite. Because neither these compounds nor their metabolites enter the brain, their primary effects on food intake occur by peripheral mechanisms.” (Sullivan A C, Gruen R K. Mechanisms of appetite modulation by drugs. Federation Proceedings 1985;44,1:139-144.) Again, it is well known that peripheral serotonin is metabolized virtually entirely peripherally. Indeed, this fact led to great concern when the compound 5-HTP was first introduced as a dietary supplement.
From the forgoing, it is abundantly clear that the inventor's anti-inflammatory claims regarding HCA not only are novel, but are unexpected.
The currently most widely accepted marker for generalized inflammation is C-reactive protein (CRP). The high predictive value of plasma C-reactive protein as a risk factor for cardiovascular events has led some researchers to support the use of CRP as a main cardiovascular risk assessment tool. Some researchers maintain that CRP taken alone shows predictive power comparable to that of total cholesterol:HDL ratios. Similarly, the ability of HMG-CoA reductase inhibitors to lower C-reactive protein levels has brought into question the mechanisms of action of the statin drugs. Because these medications lower the incidence of acute cardiovascular events as well as decreasing morbidity and mortality well before the effects of lowered LDL cholesterol can be expected to occur, the argument is that they may work independently of LDL-lowering mechanisms. More generally, the CRP serum level is an indicator of the activation of various cytokines (specifically, IL-1, TNF-α, IL-6, and interferons) that trigger systemic responses, such as leukocytosis, increases in glucocorticoid production, and so forth. Downstream and associated effects include those of fibrinogen, Th1 to Th2 ratios, microalbuminuria, COX-2, platelet activating factor (PAF), plasminogen activator inhibitor-1, and so forth.
The current invention finds that HCA acts to regulate inflammation as indicated, for example, by the lowering of plasma CRP.